How blood flow is regulated, i.e., how perfusion is matched to tissue demands and maintained despite changes in arterial pressure, is a central question in cardiovascular biology. The overall objective of the proposed studies is to develop quantitative theoretical models for blood flow regulation and oxygen transport in microvascular networks of skeletal muscle and other tissues. The models will clarify the roles of mechanisms that coordinate changes in vascular resistance, will provide a rational structure for interpreting experimental data, and may lead to improved therapeutic approaches for controlling tissue perfusion. The specific aims are: (1) To develop theoretical models to simulate the autoregulatory response of microvascular networks to changes in arterial pressure, and to compare predictions with experimental data. Networks ranging from a representative flow pathway to realistic structures observed by intravital microscopy will be considered. Effects of myogenic, metabolic, shear-dependent and conducted responses will be included. Predictions will be compared with whole-organ data on flow autoregulation in skeletal muscle and other tissues. (2) To develop theoretical models to simulate the regulation of blood flow by microvascular networks in responses to changes in metabolic demand, and to compare predictions with experimental data. The role of ATP release by red blood cells in flow regulation will be analyzed. A preliminary model describing this mechanism in a single segment will be extended to more realistic network structures. The relative roles of conducted responses along vessel walls and diffusive coupling between venules and associated arterioles will be assessed using simulations. Predicted relationships between blood flow and oxygen consumption will be compared with experimental data obtained in skeletal muscle. (3) To develop theoretical models to predict distributions of vascular tone in microvascular networks of skeletal muscle, and to compare these with experimental data. An integrated model for flow regulation, incorporating all the above effects and realistic information on three-dimensional network geometry, will be used to predict distributions of tissue and vessel oxygen levels and distributions of vascular tone in microvascular networks in skeletal muscle. Predictions will be compared with experimentally measured distributions in the same vascular networks.